Download MendeleyAllosteric drug transport mechanism of multidrug transporter AcrB.
Tam, H.K., Foong, W.E., Oswald, C., Herrmann, A., Zeng, H., Pos, K.M.(2021) Nat Commun 12: 3889-3889
- PubMed: 34188038
- DOI: https://doi.org/10.1038/s41467-021-24151-3
- Primary Citation of Related Structures:
6ZO5, 6ZO6, 6ZO7, 6ZO8, 6ZO9, 6ZOA, 6ZOB, 6ZOC, 6ZOD, 6ZOE, 6ZOF, 6ZOG, 6ZOH - PubMed Abstract:
Gram-negative bacteria maintain an intrinsic resistance mechanism against entry of noxious compounds by utilizing highly efficient efflux pumps. The E. coli AcrAB-TolC drug efflux pump contains the inner membrane H + /drug antiporter AcrB comprising three functionally interdependent protomers, cycling consecutively through the loose (L), tight (T) and open (O) state during cooperative catalysis. Here, we present 13 X-ray structures of AcrB in intermediate states of the transport cycle. Structure-based mutational analysis combined with drug susceptibility assays indicate that drugs are guided through dedicated transport channels toward the drug binding pockets. A co-structure obtained in the combined presence of erythromycin, linezolid, oxacillin and fusidic acid shows binding of fusidic acid deeply inside the T protomer transmembrane domain. Thiol cross-link substrate protection assays indicate that this transmembrane domain-binding site can also accommodate oxacillin or novobiocin but not erythromycin or linezolid. AcrB-mediated drug transport is suggested to be allosterically modulated in presence of multiple drugs.
Organizational Affiliation:
Institute of Biochemistry, Goethe-University Frankfurt, Frankfurt am Main, Germany. [email protected].
